The present invention relates to methods for determining the optimum location for placement of an intraocular drug delivery system (i.e. an implant) containing a therapeutic agent for treating an ocular condition, particularly drug delivery systems comprised of a biodegradable polymer and a therapeutic agent for the treatment of a retinal disease or condition. Additionally, the present invention relates to methods for determining the optimal amount of a therapeutic agent to load into an intraocular drug delivery device to effectively treat an ocular condition.
An ocular condition can include a disease, aliment or condition which affects or involves the eye or one of the parts or regions of the eye. Broadly speaking the eye includes the eyeball and the tissues and fluids which constitute the eyeball, the periocular muscles (such as the oblique and rectus muscles) and the portion of the optic nerve which is within or adjacent to the eyeball. FIG. 1 is a schematic diagram of the human eye, from which it can be seen that the anterior segment is the front third of the eye (those portions of the eye in front of the vitreous humour) including the iris, cornea, ciliary body and lens. The posterior segment of the eye then contains the vitreous humour, retina, choroids and the optic nerve. FIG. 2 is a cross sectional view of the eye showing the positions of the macula (an oval yellow spot near the center of the retina, with the fovea being the center most part of the macula), retina, and retinal blood vessels.
An anterior ocular condition is a disease, ailment or condition which affects or which involves an anterior (i.e. front of the eye) ocular region or site, such as a periocular muscle, an eye lid or an eye ball tissue or fluid which is located anterior to the posterior wall of the lens capsule or ciliary muscles. Thus, an anterior ocular condition primarily affects or involves, the conjunctiva, the cornea, the conjunctiva, the anterior chamber, the iris, the posterior chamber (behind the retina but in front of the posterior wall of the lens capsule), the lens or the lens capsule and blood vessels and nerve which vascularize or innervate an anterior ocular region or site. A posterior ocular (also referred to herein synonymously as a “posterior segment”) condition is a disease, ailment or condition which primarily affects or involves a posterior ocular region or site such as choroid or sclera (in a position posterior to a plane through the posterior wall of the lens capsule), vitreous, vitreous chamber, retina, optic nerve (i.e. the optic disc), and blood vessels and nerves which vascularize or innervate a posterior ocular (or posterior segment) region or site.
Thus, a posterior ocular condition can include a disease, ailment or condition, such as for example, macular degeneration (such as non-exudative age related macular degeneration and exudative age related macular degeneration); choroidal neovascularization; acute macular neuroretinopathy; macular edema (such as cystoid macular edema and diabetic macular edema); Behcet's disease, retinal disorders, diabetic retinopathy (including proliferative diabetic retinopathy); retinal arterial occlusive disease; central retinal vein occlusion; uveitis (including intermediate and anterior uveitis); retinal detachment; ocular trauma which affects a posterior ocular site or location; a posterior ocular condition caused by or influenced by an ocular laser treatment; posterior ocular conditions caused by or influenced by a photodynamic therapy; photocoagulation; radiation retinopathy; epiretinal membrane disorders; branch retinal vein occlusion; anterior ischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction, retinitis pigmentosa and glaucoma. Glaucoma can be considered a posterior ocular condition because a therapeutic goal can be to prevent the loss of or reduce the occurrence of loss of vision due to damage to or loss of retinal cells or optic nerve cells (i.e. neuroprotection).
An anterior ocular condition can include a disease, ailment or condition, such as for example, aphakia; pseudophakia; astigmatism; blepharospasm; cataract; conjunctival diseases; conjunctivitis; corneal diseases; corneal ulcer; dry eye syndromes; eyelid diseases; lacrimal apparatus diseases; lacrimal duct obstruction; myopia; presbyopia; pupil disorders; refractive disorders and strabismus. Glaucoma can also be considered to be an anterior ocular condition because a clinical goal of glaucoma treatment can be to reduce a hypertension of aqueous fluid in the anterior chamber of the eye (i.e. reduce intraocular pressure).
Macular edema is a condition characterized by thickening and swelling of the macula of the eye, often caused by the collection of fluids and protein on or under the macula. This condition can significantly impair vision, such as by distorting the patient's central vision since the macula is near the center of the retina at the back of the eye. Macular edema is a major cause of visual loss in patients with diabetes, central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO). Although laser photocoagulation can reduce further vision loss in patients with diabetic macular edema (DME), vision that has already been decreased by macular edema usually does not improve by use of laser photocoagulation. Currently, there is no FDA (U.S. Food and Drug Administration) approved treatment for macular edema associated with CRVO. For macular edema associated with BRVO, grid laser photocoagulation may be an effective treatment for some patients.
Diabetic macular edema results from abnormal leakage of macromolecules, such as lipoproteins, from retinal capillaries into the extravascular space followed by an oncotic influx of water into the extravascular space. Abnormalities in the retinal pigment epithelium may also cause or contribute to diabetic macular edema. These abnormalities can allow increased fluid from the choriocapillaries to enter the retina or they may decrease the normal efflux of fluid from the retina to the choriocapillaries. The mechanism of breakdown of the blood-retina barrier at the level of the retinal capillaries and the retinal pigment epithelium may be due to changes to tight junction proteins such as occludin. Antcliff R., et al Marshall J., The pathogenesis of edema in diabetic maculopathy, Semin Opthalmol 1999; 14:223-232.
Macular edema from venous occlusive disease can result from thrombus formation at the lamina cribrosa or at an arteriovenous crossing. These changes can result in an increase in retinal capillary permeability and accompanying retinal edema. The increase in retinal capillary permeability and subsequent retinal edema can ensue from of a breakdown of the blood retina barrier mediated in part by vascular endothelial growth factor (VEGF), a 45 kD glycoprotein, as it is known that VEGF can increase vascular permeability. VEGF may regulate vessel permeability by increasing phosphorylation of tight junction proteins such as occludin and zonula occluden. Similarly, in human non-ocular disease states such as ascites, VEGF has been characterized as a potent vascular permeability factor (VPF).
Damage to the optic nerve can be due to increased pressure in the eye (i.e. elevated intraocular pressure). Elevated intraocular pressure (IOP) (ocular hypertension) can result from excess aqueous humor accumulating because the eye either produces too much or drains too little aqueous humor.
It is known to make and use an intraocular implant to treat an ocular condition. See for example U.S. Pat. Nos. 4,521,210; 4,853,224; 4,997,652; 5,164,188; 5,443,505; 5,766,242; 5,824,072; 5,869,079; 6,331,313; 6,726,918; 6,699,493; 5,501,856; 6,074,661; and; 6,369,116, and U.S. patent application Ser. Nos. 11/070,158; 11/292,544; 10/966,764; 11/117,879; 11/119,463; 11/116,698; 11/119,021; 11/118,519; 11/119,001; 11/118,288; 11/119,024; 10/340,237; 10/837,357; 10/837,355; 10/837,142; 10/837,356; 10/836,911; 10/837,143; 10/837,260; 10/837,379; 10/836,880, and 10/918,597, each of which is hereby incorporated by reference.
U.S. Pat. No. 6,713,081 discloses ocular implant devices made from polyvinyl alcohol and used for the delivery of a therapeutic agent to an eye in a controlled and sustained manner. The implants may be placed subconjunctivally or intravitreally in an eye. Devices for ocular implantation are also known, such as those described in U.S. Pat. No. 6,899,717; U.S. Pat. No. 7,090,681; US 2005 0203542 and US 2005 0154399. Each of these publications is hereby incorporated by reference.
Various treatments are known for the treatment of retinal diseases, including macular edema from diabetic retinopathy, venous occlusive disease and uveitis, such as treatment with corticosteroid implants. Unfortunately, known implants have been placed in the vitreous to treat an ocular condition in a somewhat haphazard manner. Thus, if an implant is inserted into the anterior vitreous (i.e. in proximity to the cilliary body and trabecular meshwork) elevated intraocular pressure and a high incidence of cataract can result. For example, drug (therapeutic agent) exposure to the anterior segment can lead to myocilin accumulation in the trabecular meshwork cells, leading to undesired elevation in intraocular pressure (10P). On the other hand, placing the implant in the posterior vitreous can deliver an excess of the therapeutic agent contained by the implant to the target retinal tissues.
A recent study has shown that invitreal treatment with Kenalog® (4 mg triamcinalone) can result in about 15 to 30% of the patients at 6 months having IOP of ≧10 mm Hg. Additionally, treatment with intravitreal Retisert™ (about 120 or 480 μg of fluocinolone) released over 8 months or longer can result in 59% of patients having IOP increase of a ≧10 mm HG. Furthermore, treatment with intravitreal POSURDEX® (700 μg dexamethasone released over about 1 to 2 months) can result in about 15% of patients having an IOP increase of a ≧10 mm Hg. (see Jaffe et al, Ophthalmology, 2006; 113:1020-1027). Determination of an optimal intraviteal implant placement location and/or the amount of therapeutic agent to load in the implant may permit reduction or elimination of these undesirable side effects subsequent to intravitreal administration of a drug delivery system.
What is needed therefore is a method for determining the optimal location for an intraocular implant which can deliver a therapeutically effective amount of an active agent to the desired tissue (e.g. retinal tissue) over a sustained period without causing undesirable side effects or with reduced side effects.